PD-L1 tumor-intrinsic signaling and its therapeutic implication in triple-negative breast cancer
Chunhua Chen, Shiheng Li, Junli Xue, Manlong Qi, Xin Liu, Yan Huang, Jinghua Hu, Haidong Dong, Kun Ling
Chunhua Chen, Shiheng Li, Junli Xue, Manlong Qi, Xin Liu, Yan Huang, Jinghua Hu, Haidong Dong, Kun Ling
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Research Article Oncology Therapeutics

PD-L1 tumor-intrinsic signaling and its therapeutic implication in triple-negative breast cancer

Abstract

Although the immune checkpoint role of programmed death ligand 1 (PD-L1) has been established and targeted in cancer immunotherapy, the tumor-intrinsic role of PD-L1 is less appreciated in tumor biology and therapeutics development, partly because of the incomplete mechanistic understanding. Here we demonstrate a potentially novel mechanism by which PD-L1 promotes the epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) cells by suppressing the destruction of the EMT transcription factor Snail. PD-L1 directly binds to and inhibits the tyrosine phosphatase PTP1B, thus preserving p38-MAPK activity that phosphorylates and inhibits glycogen synthase kinase 3β (GSK3β). Via this mechanism, PD-L1 prevents the GSK3β-mediated phosphorylation, ubiquitination, and degradation of Snail and consequently promotes the EMT and metastatic potential of TNBC. Significantly, PD-L1 antibodies that confine the tumor-intrinsic PD-L1/Snail pathway restricted TNBC progression in immunodeficient mice. More importantly, targeting both tumor-intrinsic and tumor-extrinsic functions of PD-L1 showed strong synergistic tumor suppression effect in an immunocompetent TNBC mouse model. Our findings support that PD-L1 intrinsically facilitates TNBC progression by promoting the EMT, and this potentially novel PD-L1 signaling pathway could be targeted for better clinical management of PD-L1–overexpressing TNBCs.

Authors

Chunhua Chen, Shiheng Li, Junli Xue, Manlong Qi, Xin Liu, Yan Huang, Jinghua Hu, Haidong Dong, Kun Ling

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Figure 6

PD-L1 mediates a tumor-intrinsic signaling that can be activated by PD-1.

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PD-L1 mediates a tumor-intrinsic signaling that can be activated by PD-1...
(A–C) Cells were subjected to immunoblotting with indicated antibodies. (A) PD-L1 is necessary for the activation of p38-MAPK by extracellular stimuli. MDA-MB-231 cells were transfected with control or PD-L1 siRNAs for 48 hours, serum-starved overnight, and then treated with FBS (10%) for indicated amount of time. (B) PD-1 activates p38-MAPK in a PD-L1–dependent manner. Control or PD-L1–depleted MDA-MB-231 cells were treated with PBS or PD-1 (0.5 μg/mL) for 15 minutes. (C) PD-1 treatment increased the protein levels of Snail in MDA-MB-231 cells. Cells were treated with PBS or PD-1 for 10 or 30 minutes. (A and C) The relative activity of p38 and protein level of Snail were quantified. Data (n = 3 independent experiments) were plotted as mean ± SEM and statistically analyzed using unpaired 2-tailed Student’s t test with (C) or without (A) the P value adjusted by Bonferroni’s method. N.S., no significant difference; *, P < 0.05; **, P < 0.01; ***, P < 0.001. (D) PD-L1 is required for p38 activation and Snail expression in vivo. MDA-MB-231 tumors grown in NOD/SCID mice as described in Figure 2 were collected and processed for immunohistochemistry staining to determine p38 activity and Snail expression in tandem tissue slides. Power of eyepiece: 10×; power of objective: 20×. Positive cells were counted in >10 fields/slide/mice, averaged, and plotted as mean ± SEM. Data (n = 6 mice/group) were statistically analyzed using unpaired 2-tailed Student’s t test with the P value adjusted by Bonferroni’s method. N.S., no significant difference; *, P < 0.05; **, P < 0.01.